Hyperbaric oxygen in children with cerebral palsy: A systematic review of effectiveness and safety

Purpose To report current evidence regarding the effectiveness of hyperbaric oxygen therapy (HBOT) on the impairments presented by children with cerebral palsy (CP), and its safety. Materials and methods PUBMED, The Cochrane Library, Google Scholar, and the Undersea and Hyperbaric Medical Society database were searched by two reviewers. Methodological quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database assessment scale for randomized controlled trials (RCTs) and the modified Downs and Black (m-DB) evaluation tool for non RCTs. A meta-analysis was performed where applicable for RCTs. Results Five RCTs were identified. Four had a high level of evidence. Seven other studies were observational studies of low quality. All RCTs used 100% O2, 1.5 to 1.75 ATA, as the treatment intervention. Pressurized air was the control intervention in 3 RCTs, and physical therapy in 2. In all but one RCTs, similar improvements were observed regarding motor and/or cognitive functions, in the HBOT and control groups. Adverse events were mostly of mild severity, the most common being middle ear barotrauma (up to 50% of children). Conclusion There is high-level evidence that HBOT is ineffective in improving motor and cognitive functions, in children with CP. There is moderate-level evidence that HBOT is associated with a higher rate of adverse events than pressurized air in children.

Introduction hypoxia, with a key-role of hypoxia-inducible factor-1a in inflammatory sites with low oxygen levels [19]. Such inflammatory processes induced by anoxia / ischaemia would be down-regulated by HBOT [17]. In contrast with these experimental findings in vitro, there is a lack of studies demonstrating the reversibility of the damages induced by anoxia or ischaemia through HBOT in animal models of CP. In children with CP, the evidence regarding a therapeutic effect of HBOT on motor and/or cognitive impairments remains scarce. To the best of our knowledge, only one literature review has been published (2007) about its effectiveness on motor and cognitive functions in this population [8]. The evidence was considered as inadequate for establishing a significant benefit of HBOT on functional outcomes [8]. The methods and results of the studies that were included in this review have raised important controversies, and calls for more studies, addressing the issue of the control treatment, have been made [20]. Since then, the debate remains open and scientists continue to argue about HBOT in those with CP, mostly through editorials and position papers [5][6][7]20]. Recently, Novak et al. endorsed a firm position against the use of HBOT in children with CP. As several clinical studies have been published since the first review [8], it appears relevant to provide an update of the literature regarding the effects of HBOT in children with CP, in order to collect and summarize the evidence on this intervention in this population.
The primary objective of the present systematic review was to assess the effectiveness of HBOT on the impairments presented by children with CP. The secondary objective was to assess the safety of these interventions in children overall.

Search strategy
A systematic review was carried out according to the PRISMA recommendations [21]. The PRISMA checklist assessment for the present systematic review can be found as S1 Checklist. The following databases were searched independently by two authors (JL and RG): PUBMED (from 1949 to May 2021), The Cochrane Library (from 1996 to May 2021), Google Scholar (from 1898 to May 2021), and the Undersea and Hyperbaric Medical Society (UHMS from 1976 to May 2021). The PICO (Patients, Interventions, Comparison, and Outcomes) framework was used to develop literature-searching strategies. Four groups of key-words were designed. The first group was related to the pathology: cerebral palsy, diplegia, hemiplegia, quadriplegia. The second group was related to the population: child, children. The third group was related to interventions: hyperbaric oxygen therapy, hyperbaric oxygenation, hyperbaric air. The fourth group was dedicated to safety and adverse events: safety, adverse events, side effects. A first step was the combination of keywords from groups 1, 2, and 3 for the assessment of effectiveness. A second step was the combination of groups 2, 3 and 4 for the assessment of safety: in order to retain all adverse events potentially occurring in children with CP, all articles dealing with HBOT in children (and not only in children with CP) were retained for this second step. The references of the articles found were also checked to ensure exhaustiveness. 4. Outcomes: inclusion of an effectiveness-and/or safety-related outcome for HBOT or HBA; 5. Language: articles written in English.
The exclusion criteria for the articles were: 1) detailed data could not be obtained (only abstracts available), 2) animal model studies; 3) single case-reports, opinion articles, editorials, letters to the editors/comments, and review-articles.
Quality assessment and study appraisal: Assessment of the characteristics of included studies. Quality. The methodological quality of each article was independently evaluated by 2 authors (JL and RG). Any disagreement resulting from this first assessment was resolved by consensus. The quality of randomised controlled trials (RCTs) was evaluated using the Physiotherapy Evidence Database Assessment Scale (PEDro) [22]. The quality of a study was classified as 'high' (�6/10), 'fair' (4-5/10) or 'poor' (�3/10) [23]. Non-RCTs were evaluated using the modified Downs and Black (m-DB) assessment tool [24], which has been reported to be suitable for use in systematic reviews of effectiveness. This tool consists of 27 items which measure internal and external validity, bias and power. The maximum score is 28. For each item of the aforementioned scales, points were only attributed if the criterion could be explicitly found in the text of the article.
The bodies of evidence were then appraised using the GRADE evidence rating system [25]. The GRADE system rates the quality of the evidence (from high to very low) and the strength of recommendation for clinical application. Participants: information about participants (age, type of cerebral palsy, and functional level) were detailed.
Intervention. data regarding the hyperbaric intervention (content: pure oxygen or air, pressure, number and duration of sessions, total volume of the intervention) and control intervention were carefully searched through and reported.
Outcome measures. all types of outcome measures identified in the retained articles were analysed and could subsequently be sorted as: motor function, spasticity, sleep disorders, cognitive functions, independence, for effectiveness-related outcome, and safety.

Data synthesis
Data regarding the authors, year of publication, population, primary outcome measure, main results, and quality, and data related to interventions (dose, number and duration of hyperbaric treatments, total duration of treatment, and associated interventions), as well as the outcomes, were extracted by two authors (JL and RG) from each article and are presented in Table 1.
Data related to safety and adverse events are shown in Table 2. Adverse events were classified into 4 categories (mild, moderate, severe, and sentinel) according to the usual scale [26].
A meta-analysis was performed when allowed by the treatment protocols and outcome measures (i.e. quantitative outcomes using the same measurement tool, in two or more intervention groups, in at least two different studies). The results of the meta-analysis were expressed using the mean difference and its 95% confidence interval for effectiveness and using odds-ratio and its 95% CI for safety (proportion of adverse events).
The review has been registered in the international prospective register of systematic reviews (PROSPERO, REF 193424).

Selection process
The initial automatic database search yielded 6114 articles (Pubmed, N = 30; The Cochrane Library, N = 17, Google Scholar, N = 51, The UHMS, N = 6011 articles, other sources/article      ) references, N = 5). Eventually, 12 articles were retained, including 5 RCTs and 7 observational studies, written between 1989 and 2017. Data regarding the study selection process are summarized in the Flow-Chart (Fig 1).

Quality assessment
Out of the twelve studies, five were RCTs, with four high-quality RCTs [27][28][29][30] and one fairquality RCT (PEDro score = 4 [31]). The other seven studies were observational studies. Six were prospective descriptive studies with a m-DB score between 5 and 14 [32][33][34][35][36][37], and one was a retrospective study with a m-DB score of 3 [38]. The details of the PEDRO score calculations for the different RCTs can be found in S1 File, and the details of the MDB scores of the non-RCT studies can be found in S2 File.  Table 1.

Outcomes
Various outcomes were assessed in the 12 retrieved studies.

Effectiveness according to the outcome
Motor function (9 studies). Four RCTs reported the effectiveness of HBOT on motor function. All used the GMFM score, considered as the gold-standard for the assessment of motor function in children with cerebral palsy [39]. The main result of two high-quality RCT [27,29] (PEDRo score = 8 and 10) was a similar improvement of the GMFM score in the intervention and the control group (pressurized air) (+2.9 points in the HBOT group, + 3.0 points in the control group, p = 0.544) in one RCT [27], and no change in the GMFM score in any group with no between-group difference in another RCT [29]). One RCT (PEDRo score = 6,) investigated upper limb function [30], and found significant improvements of manual dexterity in both groups (assessed by the Box and Blocks test), with no between-group differences.
One recent, fair-quality RCT [31] (PEDro score 4/10,) reported a significant improvement of motor function but without providing the actual GMFM scores (96% of patients improved on the GMFM in the HBOT group vs. 37% in the control group (physiotherapy) p<0.0001).
A meta-analysis was performed based on the results from the two studies describing the pre-and post-intervention GMFM scores for HBOT vs. a control intervention [27,29]. No difference in the GMFM score change was found (mean difference = 0.14 [-1.00;1;29], see Fig 2).

PLOS ONE
Besides these four RCTs, two observational studies assessed motor function in children with CP, using the GMFM score as an outcome measure (See Table 1). One observational study ( [35], mDB = 13) compared HBOT to occupational therapy and reported an improvement of the GMFM and its sub scores, while the study by Montgomery [32] (m-DB = 10) reported no improvement on the GMFM overall but with 3 categories of the GMFM out of 5 being significantly improved.
Two observational studies [33,34], used motor function as a primary outcome measure, but without using the GMFM score (see Results in Table 1).

Spasticity (3 studies).
Three studies [30,32,38] included spasticity assessments. One RCT [30] reported a significant reduction of spasticity as assessed by the H/M ratio in the soleus muscle in both the experimental and control groups, without any between-group difference. Two before/after studies [32,38] (m-DB 3-10) reported a reduction of spasticity, assessed clinically through the MAS [32] or a subjective scale [38]. See Table 1.
Cognitive functions (5 studies). Cognitive functions were assessed in three RCTs using various outcome measures [27][28][29]: Visiospatial and verbal working memory and attention [27,28], or Test of Variables of Attention [29]. HBOT did not provide additional benefit relative to pressurized air in children with CP for the cognitive and psychological functioning, and overall independence, in any study. See Table 1.
Two before/after studies [33,36] (m-DB = 10 and 11) found a significant improvement in cognitive functions (up to 35% of children based on Mental Abilities and speech abilities as outcome measures in [33]) or language based on the spontaneous verbal production (up to 44% of children [36]).

Sleep disorders (3 studies).
Three observational studies investigated the impact of HBOT on sleep disorders (m-DB = [10][11][12][13][14], [32,36,37]. The main outcome measure was the total sleep items (TSI) from the Sleep Disturbance Scale for Children Questionnaire [40] in 2 out of 3 studies [36,37]. Both reported a significant reduction of the TSI after HBOT. Montgomery et al. [32] used a custom questionnaire completed by parents, and reported an improvement in the quality of sleep. See Table 1.
Independence (4 studies). In the two high-quality RCTs [27,29] investigating the functional performance of children with CP using the PEDI (Pediatric Evaluation of Disability Inventory) score, an improvement was reported in both the experimental group and the control group, without any between-group difference.
Safety (5 studies). Six studies assessed the adverse events occurring during / after HBOT in children [41][42][43][44][45][46] as a primary outcome measure. One of these studies specifically investigated the adverse effects of HBOT in children with CP [41], in a safety analysis based on the RCT by Collet et al. [27]: HBOT 1.75 ATA vs 1.3 ATA hyperbaric air. Middle ear barotrauma (MEB) was significantly more frequent in the HBOT group (50% of patients vs. HBT: 27.8%, relative risk = 1.5, 95% IC = 1.1-2.2, p = 0.02). A multivariate analysis did not find any factor associated with a higher risk of barotrauma. Other adverse events were rare and did not differ PLOS ONE between groups. Data from the other studies [29,[42][43][44][45][46] indicated that overall, the adverse events were mostly rare and of mild severity (See Table 2). The most frequent was middle ear barotrauma (up to 50% of cases) [41]. Less frequently, seizures, confinement anxiety, pulmonary disorders, nausea, hypoglycemia, hypotension, visual disorders and dizziness were observed. Younger age was likely to be a risk-factor for middle-ear barotrauma: in the study by Hadanny et al. [42] about adverse events in a retrospective series of 2334 patients treated with HBOT (240 children), a multivariate analysis showed that subjects under the age of 16 had a higher risk of evidenced middle ear barotrauma (adjusted odd-ratio = 2.729, 95% CI = 1.352-5.505, p = 0.005).
A meta-analysis was performed based on the results from the two controled studies describing the adverse events of HBOT vs. a control intervention in cerebral palsy [29,41]. No increase in the relative risk was found in the HBOT group. (OR: 1.50 [0. 43-5.21], see Fig 3).
Other studies assessed effectiveness of HBOT as the primary outcome measure (see above) but also reported data about adverse events. The results from the studies reporting safety are listed in Table 2.

Discussion
The results from the present systematic review are the following: first, based on three highquality RCTs [27,29,30], there is high level evidence that HBOT is ineffective in improving motor function, cognitive functions, and functional performance, compared to pressurized air or physical therapy. Secondly, based on three observational studies [32,36,37] there is very low level evidence that HBOT improves sleep disorders in children with CP. Thirdly, based on two prospective studies assessing the adverse events in a systematic way [29,42], there is conflicting evidence about whether HBOT is associated with a higher rate of side effects than 1.3 ATA air. Given these results, HBOT is not recommended in clinical practice in children with CP. The present review confirms previous conclusions that hyperbaric interventions should not be administered in standard care [5,7]. These results are in accordance with the previous systematic review, published in 2007 [8], and with the recent report endorsed by the Québec government [47].

Interventions and controls
The main result of the present systematic review is the high-level evidence that HBOT does not improve motor function compared to control interventions, though outstanding results have been reported in a lower-quality RCT [31], or in observational studies. It has to be noticed that the control intervention was variable among the 4 RCT assessing motor function: hyperbaric air in two [27,29] and physical and/or occupational therapy in two [30,31]. There has been considerable debate about the issue of the control intervention. Authors who claim for efficacy of HBOT in children with CP have stressed that the negative results of HBOT in the literature have to be reconsidered based on a potential effect of hyperbaric air, which is frequently used as the control intervention due to its similarity in the material conditions and pressure effect [48]. Pressures of about 1.3 ATA, which is the threshold from which the subject in the chamber can perceive mechanical and physiological effects, are classically used as the control, "sham" procedures in studies on HBOT. However, physiological effects have been evidenced at such pressure levels [49]. This point has led some authors to claim that the improvements in the outcomes that were observed in both the HBOT and control groups could be due to a genuine physiological effect of hyperbaric air rather than to a placebo effect [27,48]. Then, Lacey et al., designed their RCT in order to compare HBOT to hyperbaric air with reduced oxygen rate (1.5 ATA, 14% O 2 to obtain physiological blood oxygen content), and obtained similar negative results in both groups [29]. This study has been used by the majority of the paediatric community to consider the debate as ended [5,7]. However, given that any increase in pressure, even with reduced or adjusted oxygen rates, must be considered as having a potential physiological effect, its use as a placebo remains challenged, together with the conclusions of Lacey et al. [29]. Theoretically, it is possible to design future studies with an experimental design where the effects of hyperpressurization and hyperoxygenation would be differentiated, by dividing the experimental samples into, for instance, four experimental groups: one group with usual HBOT (1.5 ATM, 100% O 2 ), one group with pure oxygen at normal pressure (1.0 ATM, 100% O 2 ), one group with pressurized air and an equivalent atmospheric oxygen content (1.5 ATM, 14% O 2 ), and one control group with normal air (1.0 ATM, 21% O 2 ).

Patients
All types of clinical presentations of CP were included in the different studies of this systematic review. The influence of the vast heterogeneity of patients on the negative results in the RCTs included in the present review can be questioned. Dispersion is also apparent regarding the severity of the CP. The GMFCS level was available in only 4 out of 12 studies, and was never considered as an inclusion criterion. A wide range of age is also apparent in the studies. Finally, the aetiology of the CP and pathophysiological mechanisms of the brain injury in the children included were hardly ever detailed. Yet, given the physiological effects of hyperbaric treatments, brain lesions where hypoxia at the brain tissue level is the limiting factor of recovery have been considered as the target of HBOT in neurological indications [9]. Asl et al. [50] (not included in the present review because no clinical outcomes were measured) assessed brain perfusion, using SPECT, in 4 patients with CP aged 5 to 27 years, before and after 40 treatments with HBOT. Two patients out of four showed improved cerebral perfusion after HBOT. In stroke patients, Efrati et al. [51] showed that improvements in impairments and activity after HBOT correlated with changes in SPECT imaging, and that elevated brain activity was detected mostly in regions of alive cells (as confirmed by CT) with low activity (based on SPECT). However, the level of evidence of HBOT in other brain injuries than CP (for instance, in adult patients with acquired lesions) remains low [10,14,52,53]. It could be proposed in future studies to assess brain perfusion imaging and functional MRI, together with clinical measures, in order to determine if a sub-type of cerebral lesion (leukomalacia, stroke. . .) could be associated with a positive response to HBOT, which would be in line with its presumed effect of increasing the delivery of oxygen to the brain.

Developmental trajectories
HBOT is usually delivered on a mid or long-term period (usually 40 treatments distributed on approximately 2 months, but protocols with up to 200 treatments [31] have been used, see Table 1). With time, children with CP present a spontaneous evolution of their motor performance. In EBI and CP, the developmental trajectories must be considered, as the functional performance level varies with time, even if the brain lesions are stabilized [54]. Regarding motor function for instance, the GMFM-ER (Gross Motor Function Measure Evolution Ratio) has been proposed as an outcome measure to take the natural progression of CP children into account [55]. It is possible that this natural progression participated in the improvements observed in both groups in the RCT by Collet et al. [27] or in observational studies. From now on, we assume that the GMFM-ER should be used as the outcome measure for motor function in children with CP, rather than the GMFM, especially for interventions performed on longer periods, like HBOT. Because the natural evolution of the GMFM-66 score has been previously predicted for children with CP who were less than eight years old [55] and because the precise age of individual children in the different studies included in the present review was not available, we could not compute the GMFM-ER in the meta-analysis. As suggested by Collet et al., an alternative hypothesis to explain significant changes in all groups is that improvements on the GMFM were due to a participation effect (increased interactions at both the children and parents' level) [27]. One interesting result in the study by Lacey et al. [29] is in line with this hypothesis: while no change in cognitive and motor impairments was observed in any group, significant improvements on the PEDI were reported, without between-group differences. The improvements on the PEDI, though significant, remained below 5%, which is less than the considered threshold for clinically meaningful change (considered as 10-11% by the team who conceived and developed the scale [56]).

Safety
We chose to investigate the adverse events of hyperbaric interventions in the children population overall, rather than in children with CP only. This can be justified by the fact that the known adverse effects of HBOT can be classified as linked to the changes in pressure/volume, to the toxicity of O 2 , and to the material used [42]. They are therefore not specific to the population of children with CP. Investigating them in the whole paediatric population was chosen in order to increase the number of studies for this part of the search and to provide a better overview of the risks associated with HBOT. Adverse events was higher in children receiving HBOT than in those receiving HBT with 1.3 ATA, with a relative risk of 1.5 in the only study which investigated adverse events systematically and as the primary outcome measure [41]. However, the adverse events were similar in both groups in another RCT [29] and the metaanalysis showed no difference between HBOT and HBA. Middle ear barotrauma was by far the most frequent side effect, and could affect up to 50% of children [41] during HBOT. This is not surprising, as higher pressures were used in the HBOT interventions (1.5 to 1.75 ATA) than in the controls (1.3 ATA). Though not severe, middle ear barotrauma must be considered as a major issue in hyperbaric interventions given its high occurrence.

Limitations
The present systematic review highlights that, despite more than 30 years of experience, only few studies with good methodological quality have been published that investigated the benefits and adverse effects of HBOT in children with cerebral palsy. The quality of the evidence can be considered as moderate to high though, as the results of the three high-quality RCTs are rather consistent. Besides, the heterogeneity in the control interventions and in the outcomes impeded the conduction of meta-analyses, making the interpretation of the results difficult.
Three of the studies were carried out by the same research team [27,28,32] including two RCTs. This can introduce a bias, as the data from the same sample of children have been studied several times, and limits the external validity of the results.
Regarding adverse events, apart from the studies by Muller-Bola et al. [41] and Lacey et al. [29], no published work regarding HBOT and HBA in children with CP assessed adverse events in a systematic manner. No precise information about the type, frequency, and severity of these adverse events was available in these studies. Therefore, the conclusion of conflicting evidence about the increased risk of middle-ear barotrauma in HBOT in children is based on only two studies.

Conclusion
From this systematic review, there is high-level evidence that HBOT does not improve motor function, cognition, and functional performance in children with CP. The use of HBOT in children with CP is therefore not recommended. The safety of HBOT appears to be fair in this population, as only very few severe adverse effects have been reported in the literature. Middle ear barotrauma of minor severity is a frequent adverse event of HBOT at currently used pressure levels (1.5 to 1.75 ATA).
Although the conclusions from this systematic review appear straightforward, attention should be drawn on the fact that they are dependent on the results of the PICO (Patients, Interventions, Comparisons, Outcomes) framework used. The originality of the present review lies in the critical appraisal of the included studies. The discussion above has stressed various, important aspects of the population, treatment and control interventions, and outcome measures, that can be questioned and examined further, based on the presumed physiological impact of HBOT. Therefore, we acknowledge that some questions raised by the 15-year controversy about HBOT in CP remain unsettled, and that there is a room for improvement in the methodology of experimental studies into hyperbaric interventions in children with cerebral palsy. However, in the absence of evidence to be sought from animal studies (that have been extensively performed) or from adult research (which has also been comprehensive), this systematic review closes the debate and claims against further clinical research into HBOT in children with CP.